Ca^<2+>-Dependent Caspase Activation by Gallic Acid Derivatives

概要

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Gallic acid(GA)derivatives, 3, 4-methylenedioxyphenyl 3, 4, 5-trihydroxythiobenzoate(GD-1)and S-(3, 4-methylenedioxyphenyl)3, 4, 5-trihydroxybenzoate(GD-3), were previously reported to induce apoptosis in tumor cells with IC_<50>s of 14.5μ_M and 3.9μ_M, respectively. To elucidate the mechanism by which these gallic acid derivatives(GDs)induce apoptosis, we studied whether GD-1 and GD-3 can activate caspases. When promyelocytic leukemia HL-60RG cells were treated with GD-1 and GD-3, poly(ADP-ribose)polymerase(PARP), a substrate of caspase-3, was cleaved into 85kDa of degradative product with increasing incubation time. GA also activated PARP cleavage, which was inhibited by catalase, N-acetyl-_L^-cysteine(NAC), and intracellular Ca^<2+> chelator 1, 2-bis(2-aminophenoxyethane)-N, N, N, N'-tetraacetic acid tetrakis(acetoxymethyl ester)(BAPTA-AM), in addition to a caspase inhibitor, Z-VAD-FMK. Its inhibitory pattern was identical with that of hypoxanthine/xanthine oxidase. On the other hand, GD-1- and GD-3-induced PARP cleavage was not suppressed by catalase or NAC, but by BAPTA-AM. This suggested that the GD-elicited signaling pathway is different from GA's. Taken together, GDs activated caspase-3 following intracellular Ca^<2+> elevation independent of reactive oxygen species. Thus, it became evident that the signaling pathway leading to apoptosis was regulated by GDs in a different manner from GA.
公益社団法人日本薬学会の論文
2001-07-01